U.S. patent application number 10/463270 was filed with the patent office on 2003-12-04 for il-8 receptor antagonists.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Benson, Gregory M., Widdowson, Katherine L..
Application Number | 20030225125 10/463270 |
Document ID | / |
Family ID | 29586148 |
Filed Date | 2003-12-04 |
United States Patent
Application |
20030225125 |
Kind Code |
A1 |
Widdowson, Katherine L. ; et
al. |
December 4, 2003 |
IL-8 receptor antagonists
Abstract
This invention relates to novel phenyl ureas useful in the
treatment of disease states mediated by the chemokine,
Interleukin-3 (IL-3)
Inventors: |
Widdowson, Katherine L.;
(King of Prussia, PA) ; Benson, Gregory M.;
(Harlow, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
29586148 |
Appl. No.: |
10/463270 |
Filed: |
June 17, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10463270 |
Jun 17, 2003 |
|
|
|
10018039 |
Mar 15, 2002 |
|
|
|
10018039 |
Mar 15, 2002 |
|
|
|
PCT/US00/16510 |
Jun 15, 2000 |
|
|
|
60139673 |
Jun 16, 1999 |
|
|
|
Current U.S.
Class: |
514/310 ;
514/596 |
Current CPC
Class: |
A61K 31/17 20130101;
Y02A 50/411 20180101; Y02A 50/30 20180101 |
Class at
Publication: |
514/310 ;
514/596 |
International
Class: |
A61K 031/47; A61K
031/17 |
Claims
What is claimed is:
1. A method of treating a chemokine mediated disease state,
selected from the group consisting of malaria, restinosis,
anoiogenesis atherosclerosis, osteoporosis, gingivitis, undesired
hematopoietic stem cells release and diseases caused by respiratory
viruses herpesviruses, and hepatitis viruses, wherein the chemokine
binds to an IL-8 .alpha. or .beta. receptor in a mammal, which
comprises administerinn to said mammal an effective amount of a
compound of the formula: 18wherein X is oxygen or sulfur; R is
(CR.sub.8R.sub.8)r C(O).sub.2H, (CR.sub.8R.sub.8)r NH--C(O)R.sub.a,
(CR.sub.8R.sub.8)r C(O)NR.sub.6'R.sub.7', (CR.sub.8R.sub.8)r
NHS(O).sub.2R.sub.b, (CR.sub.8R.sub.8)r S(O).sub.2NHR.sub.c,
(CR.sub.8R.sub.8)r NHC(X.sub.2)NHR.sub.b, or a tetrazolyl ring;
X.sub.2 is oxygen or sulfur; R.sub.1 is independently selected from
hydrogen; halogen: nitro; cyano; halosubstituted C.sub.1-10 alkyl;
C.sub.1-10 alkyl; C.sub.2-10 alkenyl; C.sub.1-10 alkoxy;
halosubstituted C.sub.1-10 alkoxy; (CR.sub.8R.sub.8)q
S(O).sub.tR.sub.4; hydroxy; hydroxy C.sub.1-4alkyl; aryl; aryl
C.sub.1-4 alkyl; aryloxy; aryl C.sub.1-4 alkyloxy; heteroaryl;
heteroarylalkyl; heterocyclic, heterocyclic C.sub.1-4alkyl:
heteroaryl C.sub.1-4 alkyloxy; aryl C.sub.2-10 alkenyl; heteroaryl
C.sub.2-10 alkenyl; heterocyclic C.sub.2-10 alkenyl;
(CR.sub.8R.sub.8)qNR.sub.4R.sub.5; C.sub.2-10 alkenyl
C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.5;
(CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.10; S(O).sub.3R.sub.8;
(CR.sub.8R.sub.8)q C(O)R.sub.11; C).sub.2-10alkenyl C(O)R.sub.11;
C.sub.2-10alkenyl C(O)OR.sub.11(CR.sub.8R.sub.8)q C(O)OR.sub.12;
(CR.sub.8R.sub.8)q OC(O) R.sub.11;
(CR.sub.8R.sub.8)qNR.sub.4C(O)R.sub.11- (CR.sub.8R.sub.8)q
NHS(O).sub.2R.sub.17; (CR.sub.8R.sub.8)q S(O).sub.2NR.sub.4R.sub.5;
or two R.sub.1 moieties together may form O--(CH.sub.2).sub.sO-- or
a 5 to 6 membered saturated or unsaturated ring; and wherein the
aryl, heteroaryl, and heterocyclic containing moieties may be
optionally substituted; n is an integer having a value of 1 to 3; m
is an integer having a value of 1 to 3; q is 0, or an integer
having a value of 1 to 10; r is 0, or an integer having a value of
1 to 4; s is an integer having a value of 1 to 3; t is 0, or an
integer having a value of 1 or 2; v is an integer having a value of
1 to 4; R.sub.4 and R.sub.5 are independently hydrogen, optionally
substituted C.sub.1-4 alkyl, optionally substituted aryl,
optionally substituted aryl C.sub.1-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl C.sub.1-4alkyl,
heterocyclic, or heterocyclic C.sub.1-4 alkyl. or R.sub.4 and
R.sub.5 together with the nitrogen to which they are attached form
a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S; R.sub.6 and R.sub.7 are
independently hydrogen or a C.sub.1-4 alkyl group, or R.sub.6 and
R.sub.7 together with the nitrogen to which they are attached form
a 5 to 7 member ring which ring may optionally contain an
additional heteroatom which heteroatom is selected from oxygen,
nitrogen or sulfur; R.sub.6', and R.sub.7' are independently
hydrogen, C.sub.1-4 alkyl, aryl, arylC.sub.1-4alkyl,
arylC.sub.2-4alkenyl, heteroaryl, heteroarylC.sub.1-4alkyl,
heteroarylC.sub.2-4 alkenyl, heterocyclic, heterocyclic
C.sub.1-4alkyl, heterocyclic C.sub.2-4alkenyl moiety, provided that
one of R.sub.6' and R.sub.7' are hydrogen. but not both; Y is
independently selected from hydrogen; halogen; nitro; cyano;
halosubstituted C.sub.1-10 alkyl; C.sub.1-10 alkyl; C.sub.2-10
alkenyl; C.sub.1-10 alkoxy; halosubstituted C.sub.1-10 alkoxy;
azide; (CR.sub.8R.sub.8)q S(O).sub.tR.sub.4; hydroxy:
hydroxyC.sub.1-4alkyl; aryl; aryl C.sub.1-4 alkyl; aryloxy;
arylC.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl
C.sub.1-4 alkyloxy; heterocyclic, heterocyclic C.sub.1-4alkyl; aryl
C.sub.1-10 alkenyl; heteroaryl C.sub.2-10 alkenyl; heterocyclic
C.sub.2-10 alkenyl; (CR.sub.8R.sub.8)q NR.sub.4R.sub.5; C.sub.2-10
alkenyl C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q
C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.10;
S(O).sub.3H; S(O).sub.3R.sub.8; (CR.sub.8R.sub.8)q C(O)R.sub.11;
C.sub.2-10 alkenyl C(O)R.sub.11; C.sub.2-10 alkenyl C(O)OR.sub.11;
C(O)R.sub.11; (CR.sub.8R.sub.8)q C(O)OR.sub.12; (CR.sub.8R.sub.8)q
OC(O) R.sub.11; (CR.sub.8R.sub.8)qNR.sub.4C(O)R.sub.11- ;
(CR.sub.8R.sub.8)q NHS(O).sub.2R.sub.d; (CR.sub.8R.sub.8)q
S(O).sub.2NR.sub.4R.sub.5; or two Y moieties together may form
O--(CH.sub.2).sub.sO-- or a 5 to 6 membered saturated or
unsaturated ring; and wherein the aryl, heteroaryl, and
heterocyclic containing moieties may be optionally substituted;
R.sub.8 is independently selected from hydrogen or C.sub.1-4 alkyl;
R.sub.10 is C.sub.1-10 alkyl C(O).sub.2R.sub.8; R.sub.11 is
hydrogen, C.sub.1-4 alkyl, optionally substituted aryl, optionally
substituted aryl C.sub.1-4alkyl, optionally substituted heteroaryl,
optionally substituted heteroarylC.sub.1-4alkyl, optionally
substituted heterocyclic, or optionally substituted
heterocyclicC.sub.1-4alkyl; R.sub.12 is hydrogen, C.sub.1-10 alkyl,
optionally substituted aryl or optionally substituted arylalkyl;
R.sub.13 and R.sub.14 are independently hydrogen, optionally
substituted C.sub.1-4 alkyl, or one of R.sub.13 and R.sub.14 may be
optionally substituted aryl; R.sub.17 is C.sub.1-4alkyl, aryl,
arylalkyl, heteroaryl, heteroarylC.sub.1-4alkyl, heterocyclic, or
heterocyclicC.sub.1-4alkyl, wherein the aryl, heteroaryl and
heterocyclic rings may all be optionally substituted; R.sub.a is an
alkyl, aryl, aryl C.sub.1-4alkyl, heteroaryl, heteroaryl
C.sub.1-4alkyl, heterocyclic, or a heterocyclic C.sub.1-4alkyl
moiety, wherein all of these moieties may be optionally
substituted; R.sub.b is a NR.sub.6R.sub.7, alkyl, aryl,
arylC.sub.1-4alkyl, arylC.sub.2-4alkenyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heteroarylC.sub.2-4 alkenyl,
heterocyclic, heterocyclic C.sub.1-4alkyl, heterocyclic
C.sub.2-4alkenyl moiety, or camphor, wherein all of these moieties
may be optionally substituted. R.sub.c is alkyl, aryl,
arylC.sub.1-4alkyl, arylC.sub.2-4alkenyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heteroarylC.sub.2-4alkenyl, heterocyclic,
heterocyclic C.sub.1-4alkyl, or a heterocyclic C.sub.2-4alkenyl
moiety, all of which may be optionally substituted one to three
times independently by halogen, nitro, halosubstituted C.sub.1-4
alkyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, NR.sub.9C(O)R.sub.a,
C(O)NR.sub.6R.sub.7, S(O).sub.3H, or C(O)OC.sub.1-4 alkyl; R.sub.d
is NR.sub.6R.sub.7, alkyl, arylC.sub.1-4 alkyl, arylC.sub.2-4
alkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroarylC.sub.2-4
alkenyl, heterocyclic, or heterocyclicC.sub.1-4 alkyl, wherein the
aryl, heteroaryl and heterocyclic containing moieties may all be
optionally substituted; 19the E containing ring is optionally
selected from 20the asterix * denoting point of attachment of the
ring; R.sub.20 is W.sub.1, optionally substituted heteroaryl,
optionally substituted C.sub.5-8 cycloalkyl, optionally substituted
C.sub.1-10 alkyl, optionally substituted C.sub.2-10 alkenyl, or an
optionally substituted C.sub.2-10 alkynyl; 21the E' containing ring
is optionally selected from 22the asterix * denoting point of
attachment of the ring; or a pharmaceutically acceptable salt
thereof.
2. The method according to claim 1 wherein the R is
(CR.sub.8R.sub.8)rC(O).sub.2H.
3. The method according to claim 1 wherein R.sub.1 is halogen,
cyano, nitro, CF.sub.3, C(O)NR.sub.4R.sub.5, alkenyl
C(O)NR.sub.4R.sub.5, C(O) R.sub.4R.sub.10, alkenyl C(O)OR.sub.12,
heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or
S(O)NR.sub.4R.sub.5.
4. The method according to claim 1 wherein R.sub.20 is W.sub.1.
5. The method according to claim 1 wherein R.sub.20 is
heteroaryl.
6. The method according to claim 4 wherein Y is halogen, C.sub.1-4
alkoxy, optionally substituted aryl. optionally substituted
arylalkoxy, methylene dioxy, NR.sub.4R.sub.5, thioC.sub.1-4alkyl,
thioaryl, halosubstituted alkoxy, optionally substituted
C.sub.1-4alkyl, hydroxy alkyl.
7. The method according to claim 1 wherein R.sub.1 is mono
substituted in the 2- or 4-position, or di-substituted in the
2,4-position by an electron withdrawing moiety.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a novel group of phenyl urea
compounds processes for the preparation thereof, the use thereof in
treating IL-8, GRO.alpha., GRO.beta., GRO.gamma., NAP-2. and ENA-78
mediated diseases and pharmaceutical compositions for use in such
therapy.
BACKGROUND OF THE INVENTION
[0002] Many different names have been applied to Interleukin-8
(IL-8), such as neutrophil attractant/activation protein-1 (NAP-1),
monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil
activating factor (NAF), and T-cell lymphocyte chemotactic factor.
Interleukin-8 is a chemoattractant for neutrophils, basophils, and
a subset of T-cells. It is produced by a majority of nucleated
cells including macrophages, fibroblasts, endothelial and
epithelial cells exposed to TNF, IL-1.alpha.L-1.beta. or LPS, and
by neutrophils themselves when exposed to LPS or chemotactic
factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84,
1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J.
Immunol. 144, 2223 (1990); Strieter, et al, Science 243, 1467
(1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al, J.
Immunol. 148, 3216 (1992).
[0003] GRO.alpha., GRO.beta., GRO.gamma. and NAP-2 also belong to
the chemokine .alpha. family. Like IL-8 these chemokines have also
been referred to by different names. For instance GRO.alpha.,
.beta., .gamma. have been referred to as MGSA.alpha., .beta. and
.gamma. respectively (Melanoma Growth Stimulating Activity), see
Richmond et al, J. Cell Physiology 129, 375 (1986) and Chang et al,
J. Immunol 148, 451 (1992). All of the chemokines of the
.alpha.-family which possess the ELR motif directly preceding the
CXC motif bind to the IL-8 .beta. receptor.
[0004] IL-8, GRO.alpha., GRO.beta., GRO.gamma., NAP-2 and ENA-78
stimulate a number of functions in vitro. They have all been shown
to have chemoattractant properties for neutrophils, while IL-8 and
GRO.alpha. have demonstrated T-lymphocytes, and basophiles
chemotactic activity. In addition IL-8 can induce histamine release
from basophils from both normal and atopic individuals GRO.alpha.
and IL-8 can in addition, induce lysozomal enzyme release and
respiratory burst from neutrophils. IL-8 has also been shown to
increase the surface expression of Mac-1 (CD11b/CD18) on
neutrophils without de novo protein synthesis. This may contribute
to increased adhesion of the neutrophils to vascular endothelial
cells. Many known diseases are characterized by massive neutrophil
infiltration. As IL-8, GRO.alpha., GRO.beta., GRO.gamma. and NAP-2
promote the accumulation and activation of neutrophils, these
chemokines have been implicated in a wide range of acute and
chronic inflammatory disorders including psoriasis and rheumatoid
arthritis, Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et
al, Crit. Rev. Immunol 12, 17 (1992); Oppenheim et al, Annu. Rev.
Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463
(1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);
Donnely et al., Lancet 341. 643 (1993). In addition the ELR
chemokines (those containing the amino acids ELR motif just prior
to the CXC motif) have also been implicated in angiostasis.
Strieter et al., Science 258, 1798(1992).
[0005] In vitro, IL-8, GRO.alpha., GRO.beta., GRO.gamma., and NAP-2
induce neutrophil shape change, chemotaxis, granule release, and
respiratory burst, by binding to and activating receptors of the
seven-transmembrane, G-protein-linked family, in particular by
binding to IL-8 receptors, most notably the .beta.-receptor. Thomas
et al., J. Biol. Chem. 266, 14839(1991); and Holmes et al., Science
253, 1278(1991). The development of non-peptide small molecule
antagonists for members of this receptor family has precedent. For
a review see R. Freidinzer in: Progress in Drug Research, Vol. 40,
pp. 33-98. Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor
represents a promising target for the development of novel
anti-inflammatory agents.
[0006] Two high affinity human IL-8 receptors (77% homology) have
been characterized: IL-8R.alpha., which binds only IL-8 with high
affinity, and IL-8R.beta., which has high affinity for IL-8 as well
as for GRO.alpha., GRO.beta., GRO.gamma. and NAP-2. See Holmes et
al., supra: Murphy et al., Science 253, 1280 (1991): Lee et al., J.
Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267,
25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283
(1993).
[0007] There remains a need for treatment, in this field, for
compounds which are capable of binding to the IL-8 .alpha. or
.beta. receptor. Therefore, conditions associated with an increase
in IL-8 production (which is responsible for chemotaxis of
neutrophil and T-cells subsets into the inflammatory site) would
benefit by compounds which are inhibitors of IL-8 receptor
binding.
SUMMARY OF THE INVENTION
[0008] This invention provides for a method of treating a chemokine
mediated disease, wherein the chemokine is one which binds to an
IL-8 .alpha. or .beta. receptor and which method comprises
administering an effective amount of a compound of to Formula (I)
or a pharmaceutically acceptable salt thereof. In particular the
chemokine is IL-8.
[0009] This invention also relates to a method of inhibiting the
binding of IL-8 to its receptors in a mammal in need thereof which
comprises administering to said mammal an effective amount of a
compound of Formula (I).
[0010] Compounds of Formula (I) useful in the present invention are
represented by the structure: 1
[0011] wherein
[0012] X is oxygen or sulfur;
[0013] R is (CR.sub.8R.sub.8)r C(O).sub.2H, (CR.sub.8R.sub.8)r
NH--C(O)R.sub.a, (CR.sub.8R.sub.8)r C(O)NR.sub.6R.sub.7,
(CR.sub.8R.sub.8)rNHS(O).sub.2R.sub.b, (CR.sub.8R.sub.8)r
S(O).sub.2NHR.sub.c. (CR.sub.8R.sub.8)r NHC(X.sub.2)NHR.sub.b, or a
tetrazolyl ring;
[0014] X.sub.2 is oxygen or sulfur;
[0015] R.sub.1 is independently selected from hydrogen; halogen;
nitro; cyano; halosubstituted C.sub.1-10 alkyl; C.sub.1-10 alkyl;
C.sub.2-10 alkenyl; C.sub.1-10 alkoxy; halosubstituted C.sub.1-10
alkoxy; azide; (CR.sub.8R.sub.8)q S(O).sub.tR.sub.4; hydroxy;
hydroxy C.sub.1-4alkyl; aryl; aryl C.sub.1-4 alkyl; aryloxy; aryl
C.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic,
heterocyclic C.sub.1-4alkyl; heteroaryl C.sub.1-4 alkyloxy; aryl
C.sub.2-10 alkenyl; heteroaryl C.sub.2-10 alkenyl; heterocyclic
C.sub.2-10 alkenyl; (CR.sub.8R.sub.8)q NR.sub.4R.sub.5; C.sub.2-10
alkenyl C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q
C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.10;
S(O).sub.3R.sub.8; (CR.sub.8R.sub.8)q C(O)R.sub.11; C.sub.2-10
alkenyl C(O)R.sub.11; C.sub.2-10 alkenyl
C(O)OR.sub.11(CR.sub.8R.sub.8)q C(O)OR.sub.12; (CR.sub.8R.sub.8)q
OC(O) R.sub.11; (CR.sub.8R.sub.8)q NR.sub.4C(O)R.sub.11;
(CR.sub.8R.sub.8)q NHS(O).sub.2R.sub.17; (CR.sub.8R.sub.8)q
S(O).sub.2NR.sub.4R.sub.5; or two R.sub.1 moieties together may
form O--(CH.sub.2).sub.sO-- or a 5 to 6 membered saturated or
unsaturated ring; and wherein the aryl, heteroaryl, and
heterocyclic containing moieties may be optionally substituted;
provided that there is no ionizable hydrogen having a pKa of 3 to
10 in the 2-position of the phenyl ring;
[0016] n is an integer having a value of 1 to 3;
[0017] m is an integer having a value of 1 to 3;
[0018] q is 0, or an integer having a value of 1 to 10;
[0019] r is 0 or an integer of 1 to 4;
[0020] s is an integer having a value of 1 to 3;
[0021] t is 0, or an integer having a value of 1 or 2;
[0022] v is an integer having a value of 1 to 4;
[0023] R.sub.4 and R.sub.5 are independently hydrogen, optionally
substituted C.sub.1-4 alkyl, optionally substituted aryl,
optionally substituted aryl C.sub.1-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl C.sub.1-4alkyl,
heterocyclic, heterocyclic C.sub.1-4 alkyl, or R.sub.4 and R.sub.5
together with the nitrogen to which they are attached form a 5 to 7
member ring which may optionally comprise an additional heteroatom
selected from O/N/S;
[0024] R.sub.6 and R.sub.7 are independently hydrogen or a
C.sub.1-4 alkyl group, or R.sub.6 and R.sub.7 together with the
nitrogen to which they are attached form a 5 to 7 member ring which
ring may optionally contain an additional heteroatom which
heteroatom is selected from oxygen, nitrogen or sulfur;
[0025] R.sub.6' and R.sub.7' are independently hydrogen, C.sub.1-4
alkyl, aryl, arylC.sub.1-4alkyl, arylC.sub.2-4alkenyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heteroarylC.sub.2-4 alkenyl,
heterocyclic, heterocyclic C.sub.1-4alkyl, heterocyclic
C.sub.2-4alkenyl moiety, provided that one of R.sub.6' and R.sub.7'
is a hydrogen, but not both;
[0026] Y is independently selected from hydrogen; halogen; nitro;
cyano; halosubstituted C.sub.1-10 alkyl: C.sub.1-10 alkyl;
C.sub.2-10 alkenyl; C.sub.1-10 alkoxy; halosubstituted C.sub.1-10
alkoxy; azide; (CR.sub.8R.sub.8)q S(O).sub.tR.sub.4; hydroxy;
hydroxyC.sub.1-4alkyl; aryl; aryl C.sub.1-4 alkyl; aryloxy;
arylC.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl
C.sub.1-4 alkyloxy; heterocyclic, heterocyclic C.sub.1-4alkyl; aryl
C.sub.2-10 alkenyl; heteroaryl C.sub.2-10 alkenyl; heterocyclic
C.sub.2-10 alkenyl; (CR.sub.8R.sub.8)q NR.sub.4R.sub.5; C.sub.2-10
alkenyl C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q
C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.10;
S(O).sub.3R.sub.8; (CR.sub.8R.sub.8)q C(O)R.sub.11; C.sub.2-10
alkenyl C(O)R.sub.11; C.sub.2-10 alkenyl C(O)OR.sub.11;
C(O)R.sub.11; (CR.sub.8R.sub.8)q C(O)OR.sub.12; (CR.sub.8R.sub.8)q
OC(O) R.sub.11; (CR.sub.8R.sub.8)qNR.sub.4C(O)R.sub.11;
(CR.sub.8R.sub.8)q NHS(O).sub.2R.sub.d; (CR.sub.8R.sub.8)q
S(O).sub.2NR.sub.4R.sub.5; or two Y moieties together may form
O--(CH.sub.2).sub.sO-- or a 5 to 6 membered saturated or
unsaturated ring; and wherein the aryl, heteroaryl, and
heterocyclic containing moieties may be optionally substituted;
[0027] R.sub.8 is independently selected from hydrogen or C.sub.1-4
alkyl;
[0028] R.sub.10 is C.sub.1-10 alkyl C(O).sub.2R.sub.8;
[0029] R.sub.11 is hydrogen, C.sub.1-4 alkyl, optionally
substituted aryl, optionally substituted aryl C.sub.1-4alkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylC.sub.1-4alkyl, optionally substituted heterocyclic, or
optionally substituted heterocyclicC.sub.1-4alkyl;
[0030] R.sub.12 is hydrogen, C.sub.1-10 alkyl, optionally
substituted aryl or optionally substituted arylalkyl;
[0031] R.sub.13 and R.sub.14 are independently hydrogen, optionally
substituted C.sub.1-4 alkyl, or one of R.sub.13 and R.sub.14 may be
optionally substituted aryl;
[0032] R.sub.17 is C.sub.1-4alkyl, aryl, arylalkyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heterocyclic, or
heterocyclicC.sub.1-4alkyl, wherein the aryl, heteroaryl and
heterocyclic rings may all be optionally substituted;
[0033] R.sub.a is an alkyl, aryl, aryl C.sub.1-4alkyl, heteroaryl,
heteroaryl C.sub.1-4alkyl, heterocyclic. or a heterocyclic
C.sub.1-4alkyl moiety, wherein all of these moieties may be
optionally substituted;
[0034] R.sub.b is a NR.sub.6R.sub.7, alkyl, aryl,
arylC.sub.1-4alkyl, arylC.sub.2-4alkenyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heteroarylC.sub.2-4 alkenyl,
heterocyclic, heterocyclic C.sub.1-4alkyl, heterocyclic
C.sub.2-4alkenyl moiety, or camphor, wherein all of these moieties
may be optionally substituted;
[0035] R.sub.c is alkyl, aryl, arylC.sub.1-4alkyl,
arylC.sub.2-4alkenyl, heteroaryl, heteroarylC.sub.1-4alkyl,
heteroarylC.sub.2-4alkenyl. heterocyclic, heterocyclic
C.sub.1-4alkyl, or a heterocyclic C.sub.2-4alkenyl moiety, wherein
all of these moieties may be optionally substituted;
[0036] R.sub.d is NR.sub.6R.sub.7, alkyl, arylC.sub.1-4 alkyl,
arylC.sub.2 -4 alkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl,
heteroarylC.sub.2-4 alkenyl, heterocyclic, heterocyclicC.sub.1-4
alkyl, wherein the aryl, heteroaryl and heterocyclic containing
rings may be optionally substituted; 2
[0037] the E containing ring is optionally selected from 3
[0038] asterix * denoting point of attachment of the ring: and
[0039] R.sub.20 is W.sub.1, optionally substituted heteroaryl,
optionally substituted C.sub.5-8 cycloalkyl, optionally substituted
C.sub.1-10 alkyl, optionally substituted C.sub.2-10 alkenyl, or an
optionally substituted C.sub.2-10 alkynyl; 4
[0040] the E' containing ring is optionally selected from 5
[0041] the asterix * denoting point of attachment of the ring;
[0042] or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0043] The compounds of Formula (I) may also be used in association
with the veterinary treatment of mammals, other than humans, in
need of inhibition of IL-8 or other chemokines which bind to the
IL-8.alpha. and .beta. receptors. Chemokine mediated diseases for
treatment, therapeutically or prophylactically, in animals include
disease states such as those noted herein in the Methods of
Treatment section.
[0044] In compounds of Formula (I), R is (CR.sub.8R.sub.8)r
C(O).sub.2H, (CR.sub.8R.sub.8)r NH---(O)R.sub.a, (CR.sub.8R.sub.8)r
C(O)NR.sub.6'R.sub.7', (CR.sub.8R.sub.8)rNHS(O).sub.2R.sub.b,
(CR.sub.8R.sub.8)r S(O).sub.2NHR.sub.c, (CR.sub.8R.sub.8)r
NHC(X.sub.2)NHR.sub.b, or a tetrazolyl ring. Each of these moieties
may be directly attached to the ring in the 3-position or through
the linker (CR.sub.8R.sub.8).sub.rto the 3-position of the
ring.
[0045] Suitably, r is 0 or an integer of 1 to 4, preferably 0.
[0046] Suitably, X.sub.2 is oxygen or sulfur, preferably oxygen.
wherein r is 0 or an integer having a value of 1 to 4.
[0047] Suitably, R.sub.6 and R.sub.7 are independently hydrogen or
a C.sub.1-4 alkyl group, or R.sub.6 and R.sub.7 together with the
nitrogen to which they are attached form a 5 to 7 member ring which
ring may optionally contain an additional heteroatom which
heteroatom is selected from oxygen, nitrogen or sulfur.
[0048] Suitably, R.sub.6' and R.sub.7' are hydrogen, C.sub.1-4
alkyl, aryl, arylC.sub.1-4alkyl, arylC.sub.2-4alkenyl. heteroaryl,
heteroarylC.sub.1-4alkyl., heteroarylC.sub.2-4 alkenyl,
heterocyclic, heterocyclic C.sub.1-4alkyl, or a heterocyclic
C.sub.2-4alkenyl moiety, provided that one of R.sub.6' and R.sub.7'
are hydrogen, but not both of R.sub.6' and R.sub.7'. All of these
moieties may be optionally substituted one to three times
independently by halogen; nitro; halosubstituted C.sub.1-4 alkyl,
such as CF.sub.3; C.sub.1-4 alkyl, such as methyl; C.sub.1-4
alkoxy, such as methoxy; NR.sub.9C(O)R.sub.a; C(O)NR.sub.6R.sub.7;
S(O).sub.3H; or C(O)OC.sub.1-4 alkyl.
[0049] Suitably R.sub.a is an alkyl, aryl, arylC.sub.1-4alkyl,
heteroaryl, heteroarylC.sub.1-4alkyl, heterocyclic, or a
heterocyclic C.sub.1-4alkyl moiety, wherein all of these moieties
may be optionally substituted as defined herein.
[0050] Suitably, R.sub.b is a NR.sub.6R.sub.7, alkyl, aryl,
arylC.sub.1-4alkyl, arylC.sub.2-4alkenyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heteroarylC.sub.2-4 alkenyl,
heterocyclic, heterocyclic C.sub.1-4alkyl, or a heterocyclic
C.sub.2-4alkenyl moiety, or camphor, wherein the alkyl, aryl,
heteroaryl and heterocyclic containing moieties may all be
optionally substituted one to three times independently by halogen;
nitro; halosubstituted C.sub.1-4 alkyl, such as CF.sub.3; C.sub.1-4
alkyl, such as methyl; C.sub.1-4 alkoxy, such as methoxy;
NR.sub.9C(O)R.sub.a; C(O)NR.sub.6R.sub.7; S(O).sub.3H; or
C(O)OC.sub.1-4 alkyl. R.sub.b is preferably an optionally
substituted phenyl, benzyl, or styryl. When R.sub.b is a heteroaryl
ring, it is preferably an optionally substituted thiazole, an
optionally substituted thienyl, or an optionally substituted
quinolinyl ring.
[0051] Suitably, R.sub.g is hydrogen or a C.sub.1-4 alkyl group,
preferably a hydrogen. When R.sub.9 is in the substituent group
NR.sub.9C(O)R.sub.a, then R.sub.a is preferably an alkyl group,
such as methyl.
[0052] Suitably R.sub.c is hydrogen, alkyl, aryl,
arylC.sub.1-4alkyl, arylC.sub.1-4alkenyl, heteroaryl,
heteroarylC.sub.1-4alkyl, heteroarylC.sub.1-4alkenyl, heterocyclic,
or heterocyclic C.sub.1-4alkyl, or a heterocyclic C.sub.1-4alkenyl
moiety, all of which may be optionally substituted one to three
times independently by halogen, nitro, halosubstituted C.sub.1-4
alkyl. C.sub.1-4 alkyl, C.sub.1-4 alkoxy. NR.sub.9C(O)R.sub.a,
C(O)NR.sub.6R.sub.7, S(O).sub.3H, or C(O)OC.sub.1-4 alkyl.
Preferably, R.sub.c is an optionally substituted phenyl. 6
[0053] Suitably, the E containing ring is an optionally substituent
which is selected from 7
[0054] wherein the asterix * denotes the point of attachment of the
ring.
[0055] In compounds of Formula (I), suitably R.sub.1 is
independently selected from hydrogen; halogen; nitro; cyano;
halosubstituted C.sub.1-10 alkyl, such as CF.sub.3; C.sub.1-10
alkyl, such as methyl, ethyl. isopropyl, or n-propyl; C.sub.2-10
alkenyl; C.sub.1-10 alkoxy, such as methoxy, or ethoxy;
halosubstituted C.sub.1-10 alkoxy, such as trifluoromethoxy; azide;
(CR.sub.8R.sub.8)q S(O).sub.tR.sub.4; hydroxy; hydroxy
C.sub.1-4alkyl, such as methanol or ethanol; aryl, such as phenyl
or naphthyl: aryl C.sub.1-4 alkyl, such as benzyl; aryloxy, such as
phenoxy; aryl C.sub.1-4 alkyloxy, such as benzyloxy; heteroaryl;
heteroarylalkyl; heteroaryl C.sub.1-4 alkyloxy; aryl C.sub.2-10
alkenyl; heteroaryl C.sub.2-10 alkenyl: heterocyclic C.sub.2-10
alkenyl; (CR.sub.8R.sub.8)qNR.sub.4R.sub.5; C.sub.2-10 alkenyl
C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.5;
(CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.10, S(O).sub.3R.sub.8 such as
S(O).sub.3H; (CR.sub.8R.sub.8)q C(O)R.sub.11; C.sub.2-10 alkenyl
C(O)R.sub.11; C.sub.2-10 alkenyl C(O)OR.sub.11; C(O)R.sub.11;
(CR.sub.8R.sub.8)q C(O)OR.sub.12; (CR.sub.8R.sub.8)qOC(O)R.sub.11;
(CR.sub.8R.sub.8)q NR.sub.4C(O)R.sub.11; (CR.sub.8R.sub.8)q
NHS(O).sub.2R.sub.17; (CR.sub.8R.sub.8)qS(O).sub.2NR.sub.4R.sub.5;
or two R.sub.1 moieties together may form O--(CH.sub.2).sub.sO-- or
a 5 to 6 membered saturated or unsaturated ring. The aryl,
heteroaryl, and heterocyclic containing moieties may all be
optionally substituted as defined herein below.
[0056] Suitable, t is 0, an integer having a value of 1 or 2.
[0057] Suitably, s is an integer having a value of 1 to 3.
[0058] Suitably, q is 0, or an integer having a value of 1 to
10.
[0059] When R.sub.1 forms a dioxybridge, s is preferably 1. When
R.sub.1 forms an additional saturated or unsaturated ring, it is
preferably a 6 membered ring resulting in a naphthylene ring
system. These saturated and unsaturated ring systems may be
optionally substituted independently, 1 to 3 times by the other
R.sub.1 moieties as defined above.
[0060] Suitably, R.sub.4 and R.sub.5 are independently hydrogen,
optionally substituted C.sub.1-4 alkyl, optionally substituted
aryl, optionally substituted aryl C.sub.1-4alkyl, optionally
substituted heteroaryl, optionally substituted heteroaryl
C.sub.1-4alkyl, heterocyclic, or heterocyclicC.sub.1-4 alkyl, or
R.sub.4 and R.sub.5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an
additional heteroatom selected from O/N/S.
[0061] R.sub.8 is suitably independently selected from hydrogen or
C.sub.1-4 alkyl.
[0062] R.sub.10 is suitably C.sub.1-10 alkyl C(O).sub.2R.sub.8,
such as CH.sub.2C(O).sub.2H or CH.sub.2C(O).sub.2CH.sub.3.
[0063] R.sub.11 is suitably independently hydrogen, C.sub.1-4
alkyl, aryl, aryl C.sub.1-4 alkyl, heteroaryl, heteroaryl
C.sub.1-4alkyl, heterocyclic, or heterocyclic C.sub.1-4alkyl.
[0064] R.sub.12 is suitably hydrogen, C.sub.1-10 alkyl, optionally
substituted aryl or optionally substituted arylalkyl.
[0065] R.sub.17 is suitably C.sub.1-4alkyl, aryl, arylalkyl,
heteroaryl, heteroarylC.sub.1-4alkyl, heterocyclic, or
heterocyclicC.sub.1-4alkyl, wherein the aryl, heteroaryl and
heterocyclic rings may all be optionally substituted.
[0066] Preferably R.sub.1 is halogen, cyano, nitro, CF.sub.3,
C(O)NR.sub.4R.sub.5, alkenyl C(O)NR.sub.4R.sub.5, C(O)
R.sub.4R.sub.10, alkenyl C(O)OR.sub.12, heteroaryl,
heteroarylalkyl, heteroaryl alkenyl, or S(O)NR.sub.4R.sub.5, and
preferably R.sub.4 and R.sub.5 are both hydrogen or one of R.sub.4
and R.sub.5 is phenyl. A preferred ring substitution for the
R.sub.1 group is in the 4-position of the phenyl ring.
[0067] When R is (CR.sub.8R.sub.8).sub.r OH,
(CR.sub.8R.sub.8).sub.r SH or (CR.sub.8R.sub.8).sub.r
NHS(O).sub.2R.sub.b than R.sub.1 is preferably substituted in the
4-position, or disubstituted in the 2,4-position.
[0068] Preferably, the R.sub.1 substituent group is an electron
withdrawing moiety, such as nitro, halogen, cyano, trifluoromethyl,
or C(O)NR.sub.4R.sub.5.
[0069] When R is a carboxylic acid, than R.sub.1 is preferably
hydrogen, or R.sub.1 is preferably substituted in the 4-position,
more preferably substituted by trifluoromethyl or chloro.
[0070] In compounds of Formula (I), suitably R.sub.13 and R.sub.14
are independently hydrogen, an optionally substituted C.sub.1-4
alkyl which may be straight or branched as defined herein, or one
of R.sub.13 and R.sub.14 is an optionally substituted aryl.
[0071] When R.sub.13 or R.sub.14 are an optionally substituted
alkyl, the alkyl moiety may be substituted one to three times
independently by halogen; halosubstituted C.sub.1-4 alkyl such as
trifluoromethyl; hydroxy; hydroxy C.sub.1-4alkyl, C.sub.1-4 alkoxy;
such as methoxy, or ethoxy; halosubstituted C.sub.1-10 alkoxy;
S(O).sub.tR.sub.4; aryl; NR.sub.4R.sub.5; NHC(O)R.sub.4;
C(O)NR.sub.4R.sub.5; or C(O)OR.sub.8.
[0072] Suitably, v is 0 or an integer having, a value of 1 to
4.
[0073] Suitably, Y is independently selected from hydrogen;
halogen; nitro; cyano; halosubstituted C.sub.1-10 alkyl; C.sub.1-10
alkyl: C.sub.2-10 alkenyl; C .sub.1-10 alkoxy; halosubstituted
C.sub.1-10 alkoxy; azide; (CR.sub.8R.sub.8)q S(O).sub.tR.sub.4;
hydroxy; hydroxyC.sub.1-4alkyl; aryl; aryl C.sub.1-4 alkyl;
aryloxy; arylC.sub.1-4 alkyloxy; heteroaryl; heteroarylalkyl;
heteroaryl C.sub.1-4 alkyloxy; heterocyclic, heterocyclic C
.sub.1-4alkyl; aryl C.sub.2-10 alkenyl; heteroaryl C.sub.2-10
alkenyl: heterocyclic C.sub.2-10 alkenyl; (CR.sub.8R.sub.8)q
NR.sub.4R.sub.5; C.sub.2-10 alkenyl C(O)NR.sub.4R.sub.5;
(CR.sub.8R.sub.8)q C(O)NR.sub.4R.sub.5; (CR.sub.8R.sub.8)q
C(O)NR.sub.4R.sub.10; S(O).sub.3H; S(O).sub.3R.sub.8, such as
S(O).sub.3H; (CR.sub.8R.sub.8)q C(O)R.sub.11; C.sub.2-10 alkenyl
C(O)R.sub.11; C.sub.2-10 alkenyl C(O)OR.sub.11; (CR.sub.8R.sub.8)q
C(O)OR.sub.12; (CR.sub.8R.sub.8)q OC(O) R.sub.11;
(CR.sub.8R.sub.8)q NR.sub.4C(O)R.sub.11; (CR.sub.8R.sub.8)q
NHS(O).sub.2R.sub.d; (CR.sub.8R.sub.8)q S(O).sub.2NR.sub.4R.sub.5
or two Y moieties together may form O--(CH.sub.2).sub.sO-- or a 5
to 6 membered saturated or unsaturated ring. The aryl, heteroaryl,
and heterocyclic containing moieties may all be optionally
substituted.
[0074] When Y forms a dioxybridge, s is preferably 1. When Y forms
an additional unsaturated ring, it is preferably 6 membered
resulting in a naphthylene ring system. These saturated and
unsaturated rings may be optionally substituted 1 to 3 times by the
other Y moieties as defined above.
[0075] Suitably, R.sub.d is a NR.sub.6R.sub.7, alkyl, aryl
C.sub.1-4 alkyl, arylC.sub.2-4 alkenyl, heteroaryl,
heteroaryl-C.sub.1-4alkyl, heteroarylC.sub.2-4 alkenyl,
heterocyclic, heterocyclicC.sub.1-4 alkyl, or heterocyclic
C.sub.2-4 alkenyl moiety, wherein the aryl, heteroaryl, and
heterocyclic containing moieties may all be optionally substituted
as defined herein.
[0076] Y is preferably a halogen, C.sub.1-4 alkoxy, optionally
substituted aryl, optionally substituted aryloxy or arylalkoxy,
methylene dioxy, NR.sub.4R.sub.5, thio C.sub.1-4alkyl, thioaryl,
halosubstituted alkoxy, optionally substituted C.sub.1-4 alkyl, or
hydroxy alkyl. Y is more preferably a mono-substituted halogen.
disubstituted halogen, mono-substituted alkoxy, disubstituted
alkoxy, methylenedioxy, aryl, or alkyl. More preferably these
groups are mono or di-substituted in the 2'-position or 2'-,
3'-position of the phenyl ring.
[0077] While Y may be substituted in any of the 5 ring positions,
preferably when R is (CR.sub.8R.sub.8)rC(O).sub.2H, Y is preferably
mono-substituted in the 2'-position or 3'-position, with the
4'-preferably being unsubstituted. If the ring is disubstituted,
when R is (CR.sub.8R.sub.8)rC(O).sub.2H, substituents are
preferably in the 2' or 3' position of a monocyclic ring. While
both R.sub.1 and Y can both be hydrogen, it is preferred that at
least one of the rings be substituted, and more preferably that
both rings are substituted.
[0078] In compounds of Formula (I), X is suitably oxygen or sulfur,
preferably oxygen.
[0079] The E and E' rings. denoted by its point of attachment
through the asterix (*) may optionally be present. If it is not
present the ring is a phenyl moiety which is substituted by the
R.sub.1 and Y terms as shown herein. The E and E' ring may be
substituted by the R.sub.1 and Y moiety, respectively, in any ring,
saturated or unsaturated, and is shown for purposes herein
substituted only in the unsaturated ring(s).
[0080] In compounds of Formula (I) R.sub.20 is W.sub.1, an
optionally substituted heteroaryl, an optionally substituted
C.sub.5-8 cycloalkyl, an optionally substituted C.sub.1-.sub.10
alkyl, an optionally substituted C.sub.2-10 alkenyl, or an
optionally substituted C.sub.2-10 alkynyl.
[0081] When R.sub.20 is an optionally substituted C.sub.5-8
cycloalkyl ring, the ring may be substituted by (Y).sub.n as
defined above.
[0082] When R.sub.20 is an optionally substituted C.sub.1-10 alkyl,
an optionally substituted C.sub.2-10 alkenyl, or an optionally
substituted C.sub.2-10 alkynyl, these moieties may be optionally
substituted one or more times independently by halogen; nitro;
cyano; halosubstituted C.sub.1-10 alkyl, such as trifluoromethyl;
C.sub.1-10 alkoxy; halosubstituted C.sub.1-10 alkoxy;
S(O).sub.tR.sub.4; hydroxy; hydroxy C.sub.1-4alkyl;; aryloxy;
arylC.sub.1-4 alkyloxy; heteroaryloxy; heteroaryl C.sub.1-4
alkyloxy; heterocyclic, heterocyclic C.sub.1-4alkyl;
heterocyclicoxy; heterocyclic C .sub.1-4 alkyloxy; NR.sub.4R.sub.5;
C(O)NR.sub.4R.sub.5; C(O)NR.sub.4R.sub.10; S(O).sub.3H;
S(O).sub.3R.sub.8; C(O)R.sub.11; C(O)OR.sub.12; OC(O)R.sub.11; or
NR.sub.4C(O)R.sub.11.
[0083] When R.sub.20 is an optionally substituted C.sub.2-10
alkenyl, or an optionally substituted C.sub.2-10 alkynyl these
moieties may also, in addition to those moieties noted above, be
optionally substituted with aryl, aryl C.sub.1-4 alkyl, heteroaryl,
or a heteroaryl C.sub.1-4 alkyl (and wherein these aryl and
heteroaryl containing rings may be optionally substituted). 8
[0084] Suitably, the E' containing ring is optionally selected from
9
[0085] In compounds of Formula (I), when R.sub.20 is a heteroaryl
(HET) ring, it is suitably a heteroaryl ring or ring system. If the
HET moiety is a multi-ring system, the ring containing the
heteroatom does not need to be directly attached to the urea moiety
or the (CR.sub.13R.sub.14).sub- .v term. All the rings in this ring
system may be optionally substituted by the (Y.sub.(n) ) term as
defined above. Preferably, the HET moiety is a pyridyl, which may
be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is
preferably a benzimidazole, dibenzothiophene, or indole ring. Other
heterocyclic rings of interest include, but are not limited to
thiophene, furan, pyrimidine, pyrrole. pyrazole, quinoline,
isoquinoline, quinazolinyl, pyridine, oxazole, thiazole,
thiadiazole, triazole, or imidazole.
[0086] R.sub.20 is preferably an optionally substituted phenyl,
allyl, C.sub.1-10 alkyl, ethoxy carbonyl ethyl, dimethylacetal,
2-methoxy isopropyl, or 2-methoxy ethyl group.
[0087] Exemplified compounds of Formula (I) include:
[0088] N-(3-Carboxyphenyl)-N'-(2-bromophenyl)urea
[0089] N-(3-Carboxymethylphenyl)-N'-(2-bromophenyl)urea
[0090] N-(3-Carboxymethylphenyl)-N'-(2,3-dichlorophenyl)urea
[0091] N-(3-Carboxyphenyl)-N'-(2,3-dichlorophenyl)urea
[0092] N-[3-(2-Carboxyethyl)phenyl]-N'-(2,3-dichlorophenyl)
urea
[0093] N-(2,4-Dichloro-3-carboxy)-N'-(2-bromophenyl) urea
[0094] N-(4-Chloro-3-carboxyphenyl)-N'-(2-bromophenyl)urea
[0095] N-(4-Chloro-3-carboxyphenyl) N'-(2.3-dichlorophenyl) urea;
and
[0096] N-(4-Chloro-3-carboxyphenyl)-N-(3-chlorophenyl)urea;
[0097] or a pharmaceutically acceptable salt thereof.
[0098] As used herein, "optionally substituted" unless specifically
defined shall mean such groups as halogen, such as fluorine,
chlorine, bromine or iodine; hydroxy; hydroxy substituted
C.sub.1-10alkyl; C.sub.1-10 alkoxy, such as methoxy or ethoxy;
S(O)m' C.sub.1-10 alkyl, wherein m' is 0, 1 or 2, such as methyl
thio, methyl sulfinyl or methyl sulfonyl; amino, mono &
di-substituted amino, such as in the NR.sub.4R.sub.5 group;
NHC(O)R.sub.4; C(O)NR.sub.4R.sub.5; C(O)OH;
S(O).sub.2NR.sub.4R.sub.5; NHS(O).sub.2R.sub.2, C.sub.1-10 alkyl,
such as methyl, ethyl, propyl, isopropyl. or t-butyl;
halosubstituted C.sub.1-10 alkyl, such CF.sub.3; an optionally
substituted aryl, such as phenyl, or an optionally substituted
arylalkyl, such as benzyl or phenethyl, optionally substituted
heterocylic, optionally substituted heterocylicalkyl, optionally
substituted heteroaryl, optionally substituted heteroaryl alkyl,
and wherein these aryl, heteroaryl, or heterocyclic moieties may be
substituted one to two times by halogen; hydroxy; hydroxy
substituted alkyl; C.sub.1-10 alkoxy; S(O).sub.m C.sub.1-10 alkyl;
amino, mono & di-C.sub.1-4 alkyl substituted amino, such as in
the NR.sub.4R.sub.5 group; C.sub.1-10 alkyl, or halosubstituted
C.sub.1-10 alkyl, such as CF.sub.3.
[0099] R.sub.2 is suitably C.sub.1-4 alkyl, aryl, aryl
C.sub.1-4alkyl, heteroaryl, heteroaryl-C.sub.1-4alkyl,
heterocyclic, or heterocyclicC.sub.1-4 alkyl.
[0100] Suitable pharmaceutically acceptable salts are well known to
those skilled in the art and include basic salts of inorganic and
organic acids, such as hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methane sulphonic acid, ethane
sulphonic acid, acetic acid, malic acid, tartaric acid, citric
acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic
acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic
acid. In addition, pharmaceutically acceptable salts of compounds
of Formula (I) may also be formed with a pharmaceutically
acceptable cation, for instance, if a substituent Croup comprises a
carboxy moiety. Suitable pharmaceutically acceptable cations are
well known to those skilled in the art and include alkaline,
alkaline earth, ammonium and quaternary ammonium cations.
[0101] The following terms, as used herein, refer to:
[0102] "halo"--all halogens, that is chloro, fluoro, bromo and
iodo.
[0103] "C.sub.1-10alkyl" or "alkyl"--both straight and branched
chain radicals of 1 to 10 carbon atoms, unless the chain length is
otherwise limited, including, but not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,
n-pentyl and the like.
[0104] "cycloalkyl" is used herein to mean cyclic radicals,
preferably of 3 to 8 carbons, including but not limited to
cyclopropyl, cyclopentyl, cyclohexyl, and the like.
[0105] "alkenyl" is used herein at all occurrences to mean straight
or branched chain radical of 2-10 carbon atoms, unless the chain
length is limited thereto, including, but not limited to ethenyl,
1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl
and the like.
[0106] "aryl"--phenyl and naphthyl;
[0107] "heteroaryl" (on its own or in any combination, such as
"heteroaryloxy", or "heteroaryl alkyl")--a 5-10 membered aromatic
ring system in which one or more rings contain one or more
heteroatoms selected from the group consisting of N, O or S, such
as, but not limited, to pyrrole, pyrazole, furan, thiophene,
quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine,
oxazole, thiazole, thiadiazole, triazole, imidazole, or
benzimidazole.
[0108] "heterocyclic" (on its own or in any combination, such as
"heterocyclicalkyl")--a saturated or partially unsaturated 4-10
membered ring system in which one or more rings contain one or more
heteroatoms selected from the group consisting of N, O, or S; such
as, but not limited to, pyrrolidine, piperidine, piperazine,
morpholine, tetrahydropyran, or imidazolidine.
[0109] "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is
used herein to mean C.sub.1-10 alkyl, as defined above, attached to
an aryl, heteroaryl or heterocyclic moiety, as also defined herein,
unless otherwise indicated.
[0110] "sulfinyl"--the oxide S (O) of the corresponding sulfide,
the term "thio" refers to the sulfide, and the term "sulfonyl"
refers to the fully oxidized S(O).sub.2 moiety.
[0111] the term "wherein two R.sub.1 moieties (or two Y moieties)
may together form a 5 or 6 membered saturated or unsaturated ring"
is used herein to mean the formation of a napthylene ring system or
a phenyl moiety having attached a 6 membered partially unsaturated
ring such as a C.sub.6 cycloalkenyl, i.e. hexene, or a C.sub.5
cycloalkenyl moiety, such as a cyclopentene ring.
Methods of Preparation
[0112] The compounds of Formula (I) may be obtained by applying
synthetic procedures, some of which are illustrated in the Schemes
below. The synthesis provided for in these Schemes is applicable
for the producing compounds of Formula (I) having a variety of
different R, R.sub.1, and aryl groups which are reacted, employing
optional substituents which are suitably protected, to achieve
compatibility with the reactions outlined herein. Subsequent
deprotection, in those cases, then affords compounds of the nature
generally disclosed. Once the urea nucleus has been established,
further compounds of these formulas may be prepared by applying
standard techniques for functional group interconversion, well
known in the art. While the schemes are shown with W and R.sub.20
as phenyl this is merely for illustration purposes only.
[0113] The desired aniline 2-scheme-1 can be synthesized by the
reduction of the corresponding nitro if it is not available
commercially. This reduction can be accomplished by a number of
reducing agents such as hydrogen and catalytic Palladium on carbon
or tin chloride in a polar solvent such as DMF or ethyl acetate.
This aniline (2-scheme 1) can then be condensed with a commercially
available isocyanate in an aprotic solvent such as DMF, DMSO or
toluene. 10
[0114] Alternately, the desired compound could synthesized by the
protection of the carboxylic acid by conditions well known in art,
such as diazomethane to form the methyl ester. This compound could
then be reduced by a number of reducing agents such as hydrogen and
catalytic Palladium on carbon or tin chloride in a polar solvent
such as DMF or ethyl acetate. Condensation with a phosgene
equivalent such as di- or triphosgene in the presence of a base
such as triethyl amine or bicarbonate would form the isocyanate
4-scheme-2. This compound could then be reacted with the desired
commercially available aniline. The carboxylic acid could then be
deprotected by conditions standard in the art, such as metal
hydroxide in a polar solvent such as THF/water, then acidified with
an acid such as HCl to form 3, scheme 2. 11
[0115] Pharmaceutically acceptable salts of compounds of Formula
(I) may be obtained in known manner, for example by treatment
thereof with an appropriate amount of acid or base in the presence
of a suitable solvent.
[0116] Another aspect of the present invention is the analogous
process for producing a compound of Formula (I) which process
comprises reacting a compound of the formula 12
[0117] wherein R, R.sub.1 and m are as defined for Formula (I),
with a compound of the formula:
--N(X)--(CR.sub.13R.sub.14).sub.v--R.sub.20;
[0118] wherein X, R.sub.13, R.sub.14, v and R.sub.20 are as defined
in Formula (I) to yield a compound of Formula (I).
[0119] Alternatively, a compound of Formula (A1) 13
[0120] wherein E, R, R.sub.1 and m are as defined for Formula (I),
or a compound of Formula (A2) 14
[0121] wherein E, R, R.sub.1 and m are as defined for Formula (I),
or may instead be reacted with a compound of the formula:
--N(X)--(CR.sub.13R.sub.14).sub.v--R.sub.20;
[0122] wherein X, R.sub.13, R.sub.14, v and R.sub.20 are as defined
in Formula (I) to yield a compound of Formula (I).
[0123] Another aspect of the present invention is the alternative
process for producing a compound of Formula (I) which process
comprises reacting a compound of the formula: 15
[0124] wherein R.sub.1, m and R are as defined for formula (I);
with a compound of the formula:
NH.sub.2--(CR.sub.13R.sub.14).sub.v--R.sub.20;
[0125] wherein R.sub.13, R.sub.14, v and R.sub.20 are as defined in
Formula (I) to yield a compound of Formula (I); and deprotecting
the R group if necessary.
[0126] As above, one may alternatively use a compound of Formula
(B1) 16
[0127] wherein E, R, R.sub.1 and m are as defined for Formula (I),
or a compound of Formula (B2) 17
[0128] wherein E, R, R.sub.1 and m are as defined for Formula (I),
or may instead be reacted with a compound of the formula:
NH.sub.2--(CR.sub.13R.sub.14).sub.v--R.sub.20;
[0129] wherein R.sub.13, R.sub.14, v and R.sub.20 are as defined in
Formula (I) to yield a compound of Formula (I); and deprotecting
the R group if necessary.
[0130] In the Examples, all temperatures are in degrees Centigrade
(.degree. C.). Mass spectra were performed upon a VG Zab mass
spectrometer using fast atom bombardment, unless otherwise
indicated. .sup.1H-NMR (hereinafter "NMR") spectra were recorded at
250 MHz or 400 MHz using a Bruker AM 250 or Am 400 spectrometer,
respectively. Multiplicities indicated are: s=singlet, d=doublet,
t=triplet, q=quartet. m=multiplet and br indicates a broad signal.
Sat. indicates a saturated solution, equiv. indicates the
proportion of a molar equivalent of reagent relative to the
principal reactant.
[0131] Flash chromatography is run over Merck Silica gel 60
(230-400 mesh).
SYNTHETIC EXAMPLES
[0132] The invention will now be described by reference to the
following examples which are merely illustrative and are not to be
construed as a limitation of the scope of the present invention.
All temperatures are given in degrees centigrade, all solvents used
herein are of the highest available purity and all reactions are
run under anhydrous conditions in an argon atmosphere unless
otherwise indicated.
Example 1
Preparation of N-(3-carboxyphenyl)-N'-(2-bromophenyl)Urea
[0133] A solution of 3-amino benzoic acid (1 equivalent
(hereinafter "eq"), 1.37 gram (hereinafter "g")) in DMF was treated
with 2-bromo phenyl isocyanate (1 eq, 1.98 g) at about 80.degree.
C. for about 2 hours. The solution was cooled and the product was
purified by recrystalization from methylene chloride and hexanes to
afford 1.28 g of the titled compound as white solid.
MS(ES)M-H=333
Example 2
Preparation of N-(3-carboxymethylphenyl)-N'-(2-bromophenyl)Urea
[0134] A solution of 3-amino phenyl acetic acid (1 eq, .151 g) in
DMF was treated with 2-bromo phenyl isocyanate (1 eq, 0.198 g) at
about 80.degree. C. for about 2 hours. The solution was cooled and
the product was purified by recrystalization from methylene,
chloride and hexanes to afford 0.32g of the titled compound as
white solid. MS(ES)M-H=347
Example 3
Preparation of
N-(3-carboxymethylphenyl)-N'-(2.3-dichlorophenyl)Urea
[0135] A solution of 3-amino phenyl acetic acid (1 eq, 151
milligrams (hereinafter "mg")) in DMF was treated with 2,3-dichloro
phenyl isocyanate (1 eq, 188 mg) at 80.degree. C. for 2 hours. The
solution was cooled and the product was purified by
recrystalization from methylene chloride and hexanes to afford 0.12
g of the titled compound as white solid. MS(ES)M-H=337
Example 4
Preparation of N-(3-carboxyphenyl)-N'-(2,3-dichlorophenyl)Urea
[0136] A solution of 3-amino benzoic acid (1 eq. 1.37 g) in DMF was
treated with 2,3-dichloro phenyl isocyanate (1 eq, 1.88 g) at
80.degree. C. for 2 hours. The solution was cooled and the product
was purified by recrystalization from methylene chloride and
hexanes to afford 1.01 g of the titled compound as white solid.
MS(ES)M-H=323.
Example 5
Preparation of N-[3-(2-carboxyethyl)phenyl]N'-(2, 3-dichlorophenyl)
Urea
[0137] a) 3-amino Dihydrocinnamic Acid
[0138] A solution of 3-nitro dihydrocinnamic acid (500 mg) in ethyl
acetate was treated with 10% Pd/C (500 mg). The resulting
suspension was flushed with hydrogen and allowed to stir overnight
at room temperature The reaction mixture was purged with argon and
then filtered through celite. The filtrate was concentrated and the
residue was recrystallized from toluene and ethyl acetate. .sup.1H
NMR (DMSO) 6.95 t (1H), 6.4 m (3 H), 2.7 t (2H), 2.45 t (2H)
[0139] b) N-[3-(2-carboxyethyl)phenyl]-N'-(2,3-dichlorophenyl)
Urea
[0140] A solution of 3-amino dihydro cinnamic acid (1 eq, 83 mg) in
DMF was treated with 2,3-dichloro phenyl isocyanate (1 eq, 94 mg)
at 80.degree. C. for 2 hours. The solution was cooled and the
product was purified by recrystalization from methylene chloride
and hexanes to afford 0.037 g of the titled compound as white
solid. .sup.1H NMR (DMSO) 9.45 s (1H), 8.47 s (1H), 8.17 d (1H),
7.31 m (4H), 7.24 t (1H), 6.88 d (1H), 2.73 t ( 2H), 2.54 t
(2H)
Example 6
Preparation of N-(2.4-dichloro-3-carboxy)-N'-(2-bromophenyl)
Urea
[0141] a) 5-amino 2,6-dichloro Benzoic Acid
[0142] A solution of 5-nitro-2,6-dichloro benzoic acid (2.0 g) in
ethyl acetate was treated with 10% Pd/C(1.5 g). The suspension was
flushed with hydrogen and allowed to stir at room temperature
overnight. The reaction mixture was purged with argon and filtered
through celite. The filtrate was concentrated and the residue was
purified by recrystalization from ethyl acetate and hexanes to
afford the title compound (0.7 g) as a white solid. .sup.1H NMR
(DMSO) 7.15 d (1H), 6.8 d (1H), 5.74 s (1H, br)
[0143] b) N-(2.4-dichloro-3-carboxy)-N'-(2-bromophenyl) Urea
[0144] A solution of 5-amino-2,6-dichloro benzoic acid (1 eq, 250
mg) in DMF was treated with 2-bromo phenyl isocyanate (1 eq, 153
uL) at 80.degree. C. for 2 hours. The solution was cooled and the
product was purified by recrystalization from methylene chloride
and hexanes to afford 35 mg of the titled compound as white solid.
MS(ES)M-H=401
Example 7
Preparation of
N-(4-chloro-3-carboxyphenyl)-N'-(2-bromophenyl)urea
[0145] A solution of 5-amino-2-chloro benzoic acid (1 eq, 1.71 g)
in DMF was treated with 2-bromo phenyl isocyanate (1 eq, 1.98 g) at
80.degree. C. for 2 hours. The solution was cooled and the product
was purified by recrystalization from methylene chloride and
hexanes to afford 0.880 g of the titled compound as white solid.
MS(ES)M-H=367
Example 8
Preparation of N-(4-chloro-3-carboxyphenyl) N'(2,3-dichlorophenyl)
Urea
[0146] A solution of 5-amino-2-chloro benzoic acid (1 eq, 1.71 g)
in DMF was treated with 2,3-dichloro phenyl isocyanate (1 eq, 1.88
g) at 80.degree. C. for 2 hours. The solution was cooled and the
product was purified by recrystalization from methylene chloride
and hexanes to afford 1.57 g, of the titled compound as white
solid. MS(ES)M-H=357
Example 9
Preparation of
N-(4-chloro-3-carboxyphenyl)-N-(3-chlorophenyl)urea
[0147] A solution of 5-amino-2-chloro benzoic acid (1 eq, 1.71 g)
in DMF was treated with 3-chloro phenyl isocyanate (1 eq, 1.53 g)
at 80.degree. C. for 2 hours. The solution was cooled and the
product was purified by recrystalization from methylene chloride
and hexanes to afford 0.66 g of the titled compound as white solid.
MS(ES)M-H=323
Method of Treatment
[0148] The compounds of Formula (I), or a pharmaceutically
acceptable salt thereof can be used in the manufacture of a
medicament for the prophylactic or therapeutic treatment of any
disease state in a human. or other mammal, which is exacerbated or
caused by excessive or unregulated IL-8 cytokine production by such
mammal's cell. such as but not limited to monocytes and/or
macrophages, or other chemokines which bind to the IL-8 .alpha. or
.beta. receptor, also referred to as the type I or type II
receptor.
[0149] Accordingly. the present invention provides a method of
treating a chemokine mediated disease, wherein the chemokine is one
which binds to an IL-8 .alpha. or .beta. receptor and which method
comprises administering an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof. In
particular, the chemokines are IL-8, GRO.alpha., GRO.beta.,
GRO.gamma., NAP-2 or ENA-78.
[0150] The compounds of Formula (I) are administered in an amount
sufficient to inhibit cytokine function, in particular IL-8,
GRO.alpha., GRO.beta., GRO.gamma., NAP-2 or ENA-78, such that they
are biologically regulated down to normal levels of physiological
function, or in some case to subnormal levels, so as to ameliorate
the disease state. Abnormal levels of IL-8, GRO.alpha., GRO.beta.,
GRO.gamma., NAP-2 or ENA78 for instance in the context of the
present invention, constitute: (i) levels of free IL-8 greater than
or equal to 1 picogram per mL; (ii) any cell associated IL-8,
GRO.alpha., GRO.beta., GRO.gamma., NAP-2 or ENA-78 above normal
physiological levels; or (iii) the presence IL-8, GRO.alpha.,
GRO.beta., GRO.gamma., NAP-2 or ENA-78 above basal levels in cells
or tissues in IL-8, GRO.alpha., GRO.beta., GRO.gamma. NAP-2 or
ENA-78 respectively, is produced.
[0151] The association of interleukin-8 and rhinovirus may be found
in articles such as: Turner,et al., Clin. Infect. Dis. (1998),
26(4), 840-846; Sanders, et al., J. Virol. (1998), 72(2), 934-942;
Sethi, et al., Clin. Exp. Immunol. (1997), 110(3), 362-369; Zhu, et
al., Am. J. Physiol. (1997), 273(4, Pt. 1), L814-L824; Terajima, et
al., Am. J. Physiol. (1997), 273(4, Pt. 1), L749-L759; Grunberg, et
al., Clin. Exp. Allergy (1997), 27(1), 36-45; and Johnston, et al.,
J. Infect. Dis. (1997), 175(2), 323-329.
[0152] The association of interleukin-8 and osteoporosis may be
found in articles such as: Streckfus et al., J. Gerontol., Ser. A
(1997), 52A(6), M343-M351; Hermann, T. WO 95/31722; and Chaudhary,
et al.. Endocrinology (Baltimore) (1992), 130(5), 2528-34.
[0153] These diseases are primarily characterized by massive
neutrophil infiltration. T-cell infiltration, or neovascular
growth, and are associated with increased IL-8. GRO.alpha.,
GRO.beta., GRO.gamma.or NAP-2 production which is responsible for
the chemotaxis of neutrophils into the inflammatory site or the
directional growth of endothelial cells. In contrast to other
inflammatory cytokines (IL-1, TNF, and IL-6), IL-8, GRO.alpha.,
GRO.beta., GRO.gamma. or NAP-2 has the unique property of promoting
neutrophil chemotaxis, enzyme release including but not limited to
elastase release as well as superoxide production and activation.
The .alpha.-chemokines but particularly, GRO.alpha., GRO.beta.,
GRO.gamma. or NAP-2, working through the IL-8 type I or II receptor
can promote the neovascularization of tumors by promoting the
directional growth of endothelial cells. Therefore, the inhibition
of IL-8 induced chemotaxis or activation would lead to a direct
reduction in the neutrophil infiltration.
[0154] Recent evidence also implicates the role of chemokines in
the treatment of HIV infections, Littleman et al., Nature 381, pp
661 (1996) and Koup et al.. Nature 381, pp 667 (1996).
[0155] The present invention also provides for a means of treating,
in an acute setting, as well as preventing, in those individuals
deemed susceptible to, CNS injuries by the chemokine receptor
antagonist compounds of Formula (I).
[0156] CNS injuries as defined herein include both open or
penetrating head trauma, such as by surgery, or a closed head
trauma injury, such as by an injury to the head region. Also
included within this definition is ischemic stroke, particularly to
the brain area.
[0157] Ischemic stroke may be defined as a focal neurologic
disorder that results from insufficient blood supply to a
particular brain area. usually as a consequence of an embolus,
thrombi, or local atheromatous closure of the blood vessel. The
role of inflammatory cytokines in this are has been emerging and
the present invention provides a mean for the potential treatment
of these injuries. Relatively little treatment, for an acute injury
such as these has been available.
[0158] Present evidence also indicates the use of IL-8 inhibitors
in the treatment of atherosclerosis. The first reference, Boisvert
et al.. J Clin Invest, 1998, 101:353-363 shows, through bone marrow
transplantation. that the absence of IL-8 receptors on stem cells
(and, therefore, on monocytes/macrophages) leads to a reduction in
the development of atherosclerotic plaques in LDL receptor
deficient mice. Additional supporting references are:
Apostolopoulos et al., Arterioscler Thromb Vasc Biol. 1996.
16:1007-1012; Liu et al., Arterioscler Thromb Vasc Biol, 1997,
17:317-323; Rus et al., Atherosclerosis. 1996, 127:263-271.; Wang
et al., J Biol Chem. 1996. 271:8837-8842; Yue et al., Eur J
Pharmacol. 1993, 240:81-84; Koch et al., Am J Pathol. 1993,
142:1423-1431.; Lee et al., Immunol Lett, 1996, 53, 109-113.; and
Terkeltaub et al., Arterioscler Thromb, 1994, 14:47-53.
[0159] TNF.alpha. is a cytokine with proinflammatory actions,
including endothelial leukocyte adhesion molecule expression.
Leukocytes infiltrate into ischemic brain lesions and hence
compounds which inhibit or decrease levels of TNF would be useful
for treatment of ischemic brain injury. See Liu et al., Stoke, Vol.
25., No. 7, pp 1481-88 (1994) whose disclosure is incorporated
herein by reference.
[0160] Models of closed head injuries and treatment with mixed
5-LO/CO agents is discussed in Shohami et al., J. of Vaisc &
Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107
(1992) whose disclosure is incorporated herein by reference.
Treatment which reduced edema formation was found to improve
functional outcome in those animals treated.
[0161] The compounds of Formula (I) are administered in an amount
sufficient to inhibit IL-8, binding to the IL-8 alpha or beta
receptors, from binding to these receptors, such as evidenced by a
reduction in neutrophil chemotaxis and activation. The discovery
that the compounds of Formula (I) are inhibitors of IL-8 binding is
based upon the effects of the compounds of Formulas (I) in the in
vitro receptor binding assays which are described herein. The
compounds of Formula (I) have been shown, in some instances, to be
dual inhibitors of both recombinant type I and type II IL-8
receptors. Preferably the compounds are inhibitors of only one
receptor, more preferably Type II.
[0162] As used herein, the term "IL-8 mediated disease or disease
state" refers to any and all disease states in which IL-8,
GRO.alpha. GRO.beta., GRO.gamma., NAP-2 or ENA-78 plays a role,
either by production of IL-8, GRO.alpha. GRO.beta., GRO.gamma.,
NAP-2 or ENA-78 themselves, or by IL-8, GRO.alpha., GRO.beta.,
GRO.gamma., NAP-2 or ENA-78 causing another monokine to be
released, such as but not limited to IL-1, IL-6 or TNF. A disease
state in which, for instance, IL-1 is a major component, and whose
production or action, is exacerbated or secreted in response to
IL-8, would therefore be considered a disease stated mediated by
IL-8.
[0163] As used herein, the term "chemokine mediated disease or
disease state" refers to any and all disease states in which a
chemokine which binds to an IL-8.alpha. or .beta. receptor plays a
role, such as but not limited IL-8, GRO.alpha., GRO.beta.,
GRO.gamma., NAP-2 or ENA-78. This would include a disease state in
which, IL-8 plays a role, either by production of IL-8 itself, or
by IL-8 causing another monokine to be released, such as but not
limited to IL-1, IL-6 or TNF. A disease state in which, for
instance. IL-1 is a major component, and whose production or
action, is exacerbated or secreted in response to IL-8, would
therefore be considered a disease stated mediated by IL-8.
[0164] Such diseases include but are not limited to psoriasis,
atopic dermatitis. arthritis, asthma, chronic obstructive pulmonary
disease, adult respiratory distress syndrome, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, stroke, septic shock,
endotoxic shock, gram negative sepsis, toxic shock syndrome,
cardiac and renal reperfusion injury, glomerulonephritis,
thrombosis, graft vs. host reaction, alzheimers disease, allograft
rejections, malaria, restinosis, angiogenesis, atherosclerosis,
osteoporosis, gingivitis, undesired hematopoietic stem cells
release and diseases caused by respiratory viruses, including but
not limited to rhinovirus and influenza virus, herpesviruses,
including but not limited to herpes simplex I and II, and hepatitis
viruses, including but not limited to Hepatitis B and Hepatitis C
virus.
[0165] As used herein, the term "cytokine" refers to any secreted
polypeptide that affects the functions of cells and is a molecule
which modulates interactions between cells in the immune,
inflammatory or hematopoietic response. A cytokine includes, but is
not limited to, monokines and lymphokines, regardless of which
cells produce them. For instance, a monokine is generally referred
to as being produced and secreted by a mononuclear cell, such as a
macrophage and/or monocyte. Many other cells however also produce
monokines, such as natural killer cells, fibroblasts, basophils,
neutrophils, endothelial cells, brain astrocytes, bone marrow
stromal cells, epidermal keratinocytes and B-lymphocytes.
Lymphokines are generally referred to as being produced by
lvmphocyte cells. Examples of cytokines include, but are not
limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6),
Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-.beta.) and
Tumor Necrosis Factor beta (TNF-.beta.).
[0166] As used herein. the term "chemokine" refers to any secreted
polypeptide that affects the functions of cells and is a molecule
which modulates interactions between cells in the immune,
inflammatory or hematopoietic response, similar to the term
"cytokine" above. A chemokine is primarily secreted through cell
transmembranes and causes chemotaxis and activation of specific
white blood cells and leukocytes, neutrophils, monocytes,
macrophages, T-cells, B-cells, endothelial cells and smooth muscle
cells. Examples of chemokines include, but are not limited to,
IL-8, GROC.alpha., GRO.beta., GRO.gamma., NAP-2, ENA-78, IP-10,
MIP-1.alpha., MIP-.beta. PF4, and MCP 1, 2, and 3.
[0167] In order to use a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in therapy, it will
normally be formulated into a pharmaceutical composition in
accordance with standard pharmaceutical practice. This invention,
therefore. also relates to a pharmaceutical composition comprising
an effective. non-toxic amount of a compound of Formula (I) and a
pharmaceutically acceptable carrier or diluent.
[0168] Compounds of Formula (I), pharmaceutically acceptable salts
thereof and pharmaceutical compositions incorporating such may
conveniently be administered by any of the routes conventionally
used for drug administration, for instance, orally, topically,
parenterally or by inhalation. The compounds of Formula (I) may be
administered in conventional dosaoe forms prepared by combining a
compound of Formula (I) with standard pharmaceutical carriers
according to conventional procedures. The compounds of Formula (I)
may also be administered in conventional dosages in combination
with a known, second therapeutically active compound. These
procedures may involve mixing, granulating and compressing or
dissolving the ingredients as appropriate to the desired
preparation. It will be appreciated that the form and character of
the pharmaceutically acceptable character or diluent is dictated by
the amount of active ingredient with which it is to be combined,
the route of administration and other well-known variables. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not deleterious
to the recipient thereof.
[0169] The pharmaceutical carrier employed may be, for example,
either a solid or liquid. Exemplary of solid carriers are lactose,
terra alba, sucrose, talc, gelatin, afar, pectin, acacia, magnesium
stearate, stearic acid and the like. Exemplary of liquid carriers
are syrup, peanut oil, olive oil, water and the like. Similarly,
the carrier or diluent may include time delay material well known
to the art, such as glyceryl mono-stearate or gyceryl distearate
alone or with a wax.
[0170] A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation can be tableted,
placed in a hard gelatin capsule in powder or pellet form or in the
form of a troche or lozenge. The amount of solid carrier will vary
widely but preferably will be from about 25 mg, to about 1 g. When
a liquid carrier is used, the preparation will be in the form of a
syrup, emulsion. soft gelatin capsule, sterile injectable liquid
such as an ampule or nonaqueous liquid suspension.
[0171] Compounds of Formula (I) may be administered topically, that
is by non-systemic administration. This includes the application of
a compound of Formula (I) externally to the epidermis or the buccal
cavity and the instillation of such a compound into the ear, eye
and nose, such that the compound does not significantly enter the
blood stream. In contrast, systemic administration refers to oral,
intravenous, intraperitoneal and intramuscular administration.
[0172] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin to the site of inflammation such as liniments, lotions,
creams, ointments or pastes, and drops suitable for administration
to the eye, ear or nose. The active ingredient may comprise, for
topical administration, from 0.001% to 10% w/w, for instance from
1% to 2% by weight of the Formulation. It may however comprise as
much as 10% w/w but preferably will comprise less than 5% w/w, more
preferably from 0.1% to 1% w/w of the Formulation.
[0173] Lotions according to the present invention include those
suitable for application to the skin or eve. An eye lotion may
comprise a sterile aqueous solution optionally containing a
bactericide and may be prepared by methods similar to those for the
preparation of drops. Lotions or liniments for application to the
skin may also include an agent to hasten drying and to cool the
skin, such as an alcohol or acetone, and/or a moisturizer such as
glycerol or an oil such as castor oil or arachis oil.
[0174] Creams, ointments or pastes according to the present
invention are semi-solid formulations of the active ingredient for
external application. They may be made by mixing the active
ingredient in finely-divided or powdered form, alone or in solution
or suspension in an aqueous or non-aqueous fluid, with the aid of
suitable machinery, with a greasy or non-greasy base. The base may
comprise hydrocarbons such as hard, soft or liquid paraffin,
glycerol, beeswax, a metallic soap; a mucilage; an oil of natural
origin such as almond, corn, arachis, castor or olive oil; wool fat
or its derivatives or a fatty acid such as steric or oleic acid
together with an alcohol such as propylene glycol or a macrogel.
The formulation may incorporate any suitable surface active agent
such as an anionic, cationic or non-ionic surfactant such as a
sorbitan ester or a polyoxyethylene derivative thereof. Suspending
agents such as natural gums, cellulose derivatives or inorganic
materials such as silicaceous silicas, and other ingredients such
as lanolin, may also be included.
[0175] Drops according to the present invention may comprise
sterile aqueous or oily solutions or suspensions and may be
prepared by dissolving the active ingredient in a suitable aqueous
solution of a bactericidal and/or fungicidal agent and/or any other
suitable preservative, and preferably including a surface active
agent. The resulting solution may then be clarified by filtration,
transferred to a suitable container which is then sealed and
sterilized by autoclaving or maintaining at 98-100.degree. C. for
half an hour. Alternatively, the solution may be sterilized by
filtration and transferred to the container by an aseptic
technique. Examples of bactericidal and fungicidal agents suitable
for inclusion in the drops are phenylmercuric nitrate or acetate
(0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate
(0.01%). Suitable solvents for the preparation of an oily solution
include glycerol, diluted alcohol and propylene glycol.
[0176] Compounds of formula (I) may be administered parenterally,
that is by intravenous, intramuscular. subcutaneous intranasal,
intrarectal, intravaginal or intraperitoneal administration. The
subcutaneous and intramuscular forms of parenteral administration
are generally preferred. Appropriate dosage forms for such
administration may be prepared by conventional techniques.
Compounds of Formula (I) may also be administered by inhalation,
that is by intranasal and oral inhalation administration.
Appropriate dosage forms for such administration, such as an
aerosol formulation or a metered dose inhaler, may be prepared by
conventional techniques.
[0177] For all methods of use disclosed herein for the compounds of
Formula (I), the daily oral dosage regimen will preferably be from
about 0.01 to about 80 mg/kg of total body weight. The daily
parenteral dosage regimen about 0.001 to about 80 mg/kg of total
body weight. The daily topical dosage regimen will preferably be
from 0.1 mg to 150 mg, administered one to four, preferably two or
three times daily. The daily inhalation dosage regimen will
preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It
will also be recognized by one of skill in the art that the optimal
quantity and spacing of individual dosages of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof will be
determined by the nature and extent of the condition being treated,
the form, route and site of administration, and the particular
patient being treated, and that such optimums can be determined by
conventional techniques. It will also be appreciated by one of
skill in the art that the optimal course of treatment, i.e., the
number of doses of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof given per day for a defined number of days,
can be ascertained by those skilled in the art using conventional
course of treatment determination tests.
[0178] The invention will now be described by reference to the
following biological examples which are merely illustrative and are
not to be construed as a limitation of the scope of the present
invention.
Biological Examples
[0179] The IL-8, and GRO-.alpha. chemokine inhibitory effects of
compounds of the present invention were determined by the following
in vitro assay:
[0180] Receptor Binding Assays:
[0181] [.sup.125I] IL-8 (human recombinant) was obtained from
Amersham Corp., Arlington Heights, Ill., with specific activity
2000 Ci/mmol. GRO-.alpha. was obtained from NEN-New England
Nuclear. All other chemicals were of analytical grade. High levels
of recombinant human IL-8 type .alpha. and .beta. receptors were
individually expressed in Chinese hamster ovary cells as described
previously (Holmes, et al., Science, 1991, 253, 1278). The Chinese
hamster ovary membranes were homogenized according to a previously
described protocol (Haour, et al., J Biol Chem., 249 pp 2195-2205
(1974)). Except that the homogenization buffer was changed to 10 mM
Tris-HCL, 1 mM MgS04, 0.5 mM EDTA (ethylene-diaminetetra-acetic
acid), 1 mMPMSF (.alpha.-toluenesulphonyl fluoride), 0.5 mg/L
Leupeptin, pH 7.5. Membrane protein concentration was determined
using Pierce Co. micro-assay kit using bovine serum albumin as a
standard. All assays were performed in a 96-well micro plate
format. Each reaction mixture contained .sup.125I IL-8 (0.25 nM) or
.sup.125I Gro-.alpha. and 0.5 .mu.g/mL of IL-8R.alpha. or 1.0
.mu.g/ml of IL-8R.alpha. membranes in 20 mM Bis-Trispropane and 0.4
mM Tris HCl buffers, pH 8.0, containing 1.2 m M MgSO.sub.4, 0.4 mM
EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, drug or compound of
interest was added which had been pre-dissolved in DMSO so as to
reach a final concentration of between 0.01 nM and 100 uM. The
assay was initiated by addition of .sup.125I-IL-8. After 1 hour at
room temperature the plate was harvested using a Torntec 96-well
harvester onto a glass fiber filtermat blocked with 1%
polyethylenimine/0.5% BSA and washed 3 times with 25 rnM NaCl, 10
mN TrisHCl, 1 mM MgSO.sub.4, 0.5 mM EDTA, 0.03% CHAPS, pH 7.4. The
filter was then dried and counted on the Betaplate liquid
scintillation counter. The recombinant IL-8 R.alpha. or Type I,
receptor is also referred to herein as the non-permissive receptor
and the recombinant IL-8 R.alpha. or Type II, receptor is referred
to as the permissive receptor.
[0182] All of the exemplified compounds of Formulas (I) noted
herein in the Synthetic Chemistry Section, Example 1 to 9,
demonstrated inhibitory in the permissive models for IL-8 receptor
inhibition. The following compounds were found to be inactive in
this assay:
N-(2,4-Dichloro-3-carboxy)-N'-(2,3-dichlorophenyl)urea;
[0183] N-(3-Carboxyphenyl)-N'-(phenyl)urea and N-(3-Methy
lcarboxyphenyl)-N'-(phenyl)urea.
[0184] Chemotaxis Assay:
[0185] The in vitro inhibitory properties of these compounds are
determined in the neutrophil chemotaxis assay as described in
Current Protocols in Immunology, vol. I, Supol 1, Unit 6.12.3.,
whose disclosure is incorporated herein by reference in its
entirety. Neutrophils where isolated from human blood as described
in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1,
whose disclosure is incorporated herein by reference in its
entirety. The chemoattractants IL-8, GRO.alpha., GRO.beta.,
GRO.gamma. and NAP-2 are placed in the bottom chamber of a 48
multiwell chamber (Neuro Probe, Cabin John, Md.) at a concentration
between 0.1 and 100 nM. The two chambers are separated by a 5 um
polycarbonate filter. When compounds of this invention are tested,
they are mixed with the cells (0.001-1000 nM) just prior to the
addition of the cells to the upper chamber. Incubation is allowed
to proceed for between about 45 and 90 min. at about 37.degree. C.
in a humidified incubator with 5% CO.sub.2. At the end of the
incubation period, the polycarbonate membrane is removed and the
top side washed, the membrane then stained using the Diff Quick
staining protocol (Baxter Products, NcGaw Park. Ill., U.S.A.).
Cells which have chemotaxed to the chemokine are visually counted
using a microscope. Generally, four fields are counted for each
sample. these numbers are averaged to give the average number of
cells which had migrated. Each sample is tested in triplicate and
each compound repeated at least four times. To certain cells
(positive control cells) no compound is added, these cells
represent the maximum chemotactic response of the cells. In the
case where a negative control (unstimulated) is desired, no
chemokine is added to the bottom chamber. The difference between
the positive control and the negative control represents the
chemotactic activity of the cells.
[0186] Elastase Release Assay:
[0187] The compounds of this invention are tested for their ability
to prevent Elastase release from human neutrophils. Neutrophils are
isolated from human blood as described in Current Protocols in
Immunology Vol. I, Suppl 1 Unit 7.23.1. PMNs 0.88.times.10.sup.6
cells suspended in Ringer's Solution (NaCl 118, KCl 4.56,
NaHCO.sub.3 25, KH.sub.2PO.sub.4 1.03, Glucose 11.1, HEPES 5 mM, pH
7.4) are placed in each well of a 96 well plate in a volume of 50
ul. To this plate is added the test compound (0.001-1000 nM) in a
volume of 50 ul, Cytochalasin B in a volume of 50 ul (20 ug/ml) and
Ringers buffer in a volume of 50 ul These cells are allowed to warm
(37.degree. C., 5% CO.sub.2, 95% RH) for 5 min. before IL-8,
GRO.alpha., GRO.beta., GRO.gamma. or NAP-2 at a final concentration
of 0.01-1000 nM was added. The reaction is allowed to proceed for
45 min. before the 96 well plate is centrifuged (800.times.g 5
min.) and 100 ul of the supernatant removed. This supernatant is
added to a second 96 well plate followed by an artificial elastase
substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla,
Calif.) to a final concentration of 6 ug/ml dissolved in phosphate
buffered saline. Immediately, the plate is placed in a fluorescent
96 well plate reader (Cytofluor 2350, Millipore, Bedford, Mass.)
and data collected at 3 min. intervals according to the method of
Nakajima et al J. Biol. Chem. 254 4027 (1979). The amount of
Elastase released from the PMNs is calculated by measuring the rate
of MeOSuc-Ala-Ala-Pro-Val-AMC degradation.
[0188] TNF-.alpha. in Traumatic Brain Injury Assay
[0189] This assay provides for examination of the expression of
tumor necrosis factor mRNA in specific brain regions, which follow
experimentally, induced lateral fluid-percussion traumatic brain
injury (TBI) in rats. Since TNF.alpha. is able to induce nerve
growth factor (NGF) and stimulate the release of other cytokines
from activated astrocytes, this post-traumatic alteration in gene
expression of TNF-.alpha. plays an important role in both the acute
and regenerative response to CNS trauma. A suitable assay may be
found in WO 97/35856 or WO 97/49286 whose disclosures are
incorporated herein by reference.
[0190] CNS Injury Model for IL-.beta. mRNA
[0191] This assay characterizes the regional expression of
interleukin-1B (IL-1B) mRNA in specific brain regions following
experimental lateral fluid-percussion traumatic brain injury (TBI)
in rats. Results from these assays indicate that following TBI, the
temporal expression of IL-3 mRNA is regionally stimulated in
specific brain regions. These regional changes in cytokines, such
as IL-1B play a role in the post-traumatic pathologic or
regenerative sequelae of brain injury. A suitable assay may be
found in WO 97/35856 or WO 97/49286 whose disclosures are
incorporated herein by reference.
[0192] In Vivo--Athereoschlerosis Assay:
[0193] In vivo models for measuring atherosclerosis in mice is
based on the assay of Paigen et al with small modifications as
described below. See Paigen B, Morrow A, Holmes P A, Mitchell D,
Williams R A. Quantitative assessment of atherosclerotic lesions in
mice. Atherosclerosis 68: 231-240 (1987); and Groot P H E, van
Vlijmen B J M, Benson G M, Hofker M H, Schiffelers R, Vidgeon-Hart
M, Havekes L M. Quantitative assessment of aortic atherosclerosis
in APOE*3 Leiden transgenic mice and its relationship to serum
cholesterol exposure. Arterioscler Thromb Vasc Biol. 16: 926-933
(1996).
[0194] Sectioning and Staining of the Aortic Sinus
[0195] Cross-sections of the aortic root are taken as has been
described previously (1,2). Briefly, the hearts are bisected just
below the level of the atria and the base of the heart plus aortic
root are taken for analysis. After equilibrating the tissue in OCT
compound overnight the hearts are immersed in OCT compound on a
cryostat chuck (Bright Instrument Company Ltd., UK) with the aorta
facing the chuck. The tissue is frozen by surrounding the chuck
with dry ice. The hearts are then sectioned perpendicular to the
axis of the aorta, starting within the heart and working in the
direction of the aorta Once the aortic root has been identified by
the appearance of the three valve leaflets, alternate 10 mm
sections are taken and mounted on gelatinised slides. Sections are
air dried for 1 hour and subsequently rinsed briefly in 60%
isopropyl alcohol. The sections are stained with Oil Red O,
counterstained with Mayer's haematoxylin, cover slipped using
glycerol elatin and sealed with nail varnish.
[0196] Quantification of Atherosclerosis in the Aortic Root
[0197] Ten alternate sections of the aortic root are imaged using
an Olympus BH-2 microscope equipped with an 4.times. objective and
a video camera (Hitachi, HV-C10). Twenty-four bit colour images are
acquired and analyzed using a PC (Datacell Pentium P5-133,
Datacell, Berks, U.K.) fitted with a framegrabbing board (Snapper,
Active Imaging Ltd, Berks. U.K.) and running Optimas software
(version 5.1, Optimas Corp.,Wash., U.S.A.). The images are captured
under identical lighting, microscope, camera and PC conditions.
Quantification of the atherosclerotic lesion areas is performed by
drawing around the lesions by hand using the Optimas software.
Colour thresholds are set that quantify the areas that are stained
red within the lesions. Absolute values for the cross-sectional
areas of the lesions and the areas stained red are obtained by
calibrating the software using an image of the grid on a
haemocytometer slide.
[0198] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0199] The above description fully discloses the invention
including preferred embodiments thereof. Modifications and
improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further
elaboration, it is believed that one skilled in the are can, using
the preceding description, utilize the present invention to its
fullest extent. Therefore the Examples herein are to be construed
as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as
follows.
* * * * *